Results from ARQ 197-209: A global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).

Abstract

LBA7502 Background: Orally administered ARQ197 is a selective, non-ATP competitive inhibitor of c-MET (MET), a receptor TK implicated in cancer cell migration, invasion, and proliferation. Dual EGFR-MET inhibition is a promising strategy for overcoming MET-mediated resistance to EGFR inhibitors. A prior phase I trial demonstrated the safety of ARQ197 plus erlotinib and suggested activity in patients (pts) with advanced NSCLC. Methods: This is a global, randomized, placebo-controlled, double-blind trial comparing erlotinib plus ARQ197 (E+A) versus erlotinib plus placebo (E+P). Archival tissue was collected for all pts for k-RAS, EGFR, and MET analyses. The primary endpoint was PFS; secondary endpoints included safety, ORR, OS, and subgroup analyses. Results: 167 pts were randomized to E+A (84 pts) or E+P (83 pts). Mean age was 63 yrs and baseline characteristics were well balanced for sex (39%/41% F); race (93%/96% white) and smoking history (20%/22% never smoker). Imbalances were seen among treatment arms in NSCLC histology (54%/64% adeno) and predictive molecular genotypes: EGFR mutations (7%/13%) and k-RAS mutations (12%/6%). Final PFS was prolonged with E+A (median = 16.1 wks) vs E+P (9.7 wks) among ITT pts (HR 0.81 [95% CI 0.57, 1.15]; p=0.23). Planned multivariable Cox regression model adjusting for prognostic factors (including histology, genotype) yielded PFS HR 0.68 (95% CI 0.47, 0.98; p<0.05). PFS improvement was particularly prominent among pts with nonsquamous histology, EGFR wild-type status, and k-RAS mutations. Preliminary safety analysis revealed no major differences between arms with AEs (≥10% of pts; all grades) including rash (64%/52%); diarrhea (48%/53%); fatigue (33%/37%); nausea (26%/26%); and anemia (14%/13%). OS, ORR, and final safety data will be analyzed at study conclusion. Conclusions: Combined with erlotinib in the treatment of second/third-line EGFR-inhibitor naïve NSCLC, ARQ-197 is well-tolerated and prolongs PFS. Particular benefit is observed among pts with non-squamous histology, k-RAS mutations, and EGFR wild-type status. [Table: see text]

Early Clinical Development of ARQ 197, a Selective, Non–ATP-Competitive Inhibitor Targeting MET Tyrosine Kinase for the Treatment of Advanced Cancers

“…SD was observed in 41 (56%) and 34 (47%) patients, yielding disease control rates of 66% and 54%, respectively (Table 2) [44].…”

“…Eligible patients were randomly assigned to receive erlotinib 150 mg qd ϩ ARQ 197 360 mg bid (n ϭ 84), or erlotinib 150 mg qd ϩ placebo (n ϭ 83; 28-day cycles in both groups) [36,44]. The primary study endpoint was PFS.…”

“…ARQ 197-209 is a recently concluded global, randomized, placebo-controlled, double-blind phase II clinical trial that evaluated erlotinib ϩ ARQ 197 compared with erlotinib ϩ placebo in second-/third-line chemotherapy-experienced, EGFR-inhibitor-naïve patients (N ϭ 167) with inoperable, locally advanced/metastatic NSCLC [36,44]. Eligible patients were randomly assigned to receive erlotinib 150 mg qd ϩ ARQ 197 360 mg bid (n ϭ 84), or erlotinib 150 mg qd ϩ placebo (n ϭ 83; 28-day cycles in both groups) [36,44].…”

Targetable “Driver” Mutations in Non Small Cell Lung Cancer

“…Recent studies have shown a randomized phase II trial, Erlotinib with ARQ197 compared to Erlotinib with placebo in patients with advanced NSCLC patients who had received at least one prior regimen with a primary endpoint being PFS. The combination arm showed better PFS 16.1 weeks versus the 9.7 weeks in patients who received Erlotinib alone [79]. Table 1 shows the list of above mentioned targets along with its respective inhibitors and details of the trial.…”

EGFR and c-Met Inhibitors are Effective in Reducing Tumorigenicity in Cancer

“…Tivantinib was shown to increase PFS from 9.7 to 16.1 weeks when given in combination with erlotinib. PFS improvement was particularly prominent among a subset of patients with nonsquamous histology, EGFR wild-type status, and k-RAS mutations [84]. A different phase II combinatorial study was conducted with 128 NSCLC patients, who had received at least one chemotherapy session, in which patients were given MetMAb (onartuzumab) intravenously along with erlotinib.…”